Preliminary results suggest the strategy could be used to transport the needed myotubularin enzyme (a type of protein) into muscle fibers in myotubularin-deficient mice and perhaps ultimately humans with X-linked myotubular myopathy.

The researchers have received MDA support to develop this strategy, which may have treatment applications for other neuromuscular diseases.

MDA-supported researchers at 4s3 Bioscience, a biotechnology company in Medford, Mass., are using a new molecular strategy to transport a potentially therapeutic protein into muscles, as an experimental treatment for X-linked myotubular myopathy (MTM), a genetic muscle disease that's generally fatal in infancy.

The treatment will be tested in a mouse model of MTM. These mice do not make myotubularin and display signs and symptoms similar to those in humans with X-linked MTM.

"This is a really exciting strategy, because it has applicability to a number of diseases," said Jane Larkindale, portfolio manager for MDA Venture Philanthropy, a division of MDA's research program that specializes in funding small biotechnology companies with innovative ideas. "We're especially thrilled that 4s3 has decided to pilot this technology in myotubular myopathy."

About the new research

X-linked MTM results from a deficiency of the enzyme myotubularin. The disease affects males and causes severe weakness and lack of muscle tone, along with respiratory insufficiency. Those who survive infancy often require a ventilator to breathe. There currently are no known therapies that address the underlying cause of the disease.

Dustin Armstrong, vice president of research at 4s3 Bioscience and the company's co-founder, is the primary investigator on the project. He's been awarded $260,291 from MDA to develop this experimental MTM treatment.

Armstrong and colleagues at 4s3 and Children's Hospital Boston will fuse a fragment of an antibody (immune-system protein) to the myotubularin protein molecule. The specific antibody fragment they'll use has been shown to be capable of entering muscle fibers from the bloodstream. Preliminary tests also suggest that the antibody fragment is nontoxic and does not interfere with the action of the protein to which it's attached.

If the myotubularin/antibody-fragment construct safely and successfully penetrates muscle tissue and allows entry of the myotubularin protein, this antibody fragment (or other fragments being developed by 4s3) could be utilized to deliver needed muscle proteins in other diseases, such as some of the muscular dystrophies or metabolic diseases of muscle.

The researchers will inject the construct intravenously into mice that, like humans with myotubular myopathy, lack functional myotubularin and show muscle weakness and other characteristics of the human disease.

The investigators then will determine whether the construct penetrates muscle fibers; whether myotubularin assumes its normal functions in the fibers; whether strength or function improve in the mice; and what, if any, toxic effects occur. (For instance, the researchers say they'll be watching the mice closely for signs of rejection of the new molecule by the immune system.

"Having the support of MDA and collaborators from Children's Hospital Boston, such as Mike Lawlor and Alan Beggs, is enormous," Armstrong said. "Myotubular myopathy represents a real unmet medical need, and we believe the enzyme replacement approach we are pursuing has a strong scientific rationale."

Armstrong noted that “the fundamental strategy of enzyme replacement therapy has been validated with approved products for other diseases on the market” — a reference to products such as Myozyme, developed by Genzyme Corp. to treat Pompe disease (acid maltase deficiency), a metabolic myopathy in MDA's program.

"Our goal is to develop a method that will 'shuttle' missing proteins into muscle more efficiently, and we're excited about this opportunity to further validate our approach and test a novel therapeutic candidate for myotubular myopathy," he said.

Meaning for families with myotubular myopathy

If the strategy is safe and effective in mice with myotubularin deficiency, the possibility that it could be developed for humans with myotubular myopathy exists.

In fact, a success with the myotubularin-deficient mice would bode well for broadening development of this antibody delivery strategy for use in other diseases, such as some muscular dystrophies and metabolic myopathies.